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ORIGINAL RESEARCH article

Front. Endocrinol.

Sec. Diabetes: Molecular Mechanisms

Volume 16 - 2025 | doi: 10.3389/fendo.2025.1627947

This article is part of the Research TopicThe Impact of GIP/GIPR on Metabolic Diseases: How the Field Is EvolvingView all 6 articles

Counterregulatory Response to Hypoglycemia During a Hypoglycemic Clamp in People with Type 2 Diabetes Treated with Tirzepatide

Provisionally accepted
Thomas  R. PieberThomas R. Pieber1*Eva  SvehlikovaEva Svehlikova2Shweta  UrvaShweta Urva3Axel  HauptAxel Haupt3Chunmei  ZhouChunmei Zhou3Tamer  CoskunTamer Coskun3Vera  HöllerVera Höller2Gabriele  FluhrGabriele Fluhr2Chrisanthi  A. KaranikasChrisanthi A. Karanikas3Zvonko  MilicevicZvonko Milicevic4Edward  J. PrattEdward J. Pratt5
  • 1Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz, Graz, Austria
  • 2Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
  • 3Eli Lilly and Company, Indianapolis, United States
  • 4Eli Lilly and Company, Vienna, Austria
  • 5Lilly Centre for Clinical Pharmacology Pte Ltd, Biopolis, Singapore

The final, formatted version of the article will be published soon.

Introduction: To evaluate counterregulatory hormonal responses during a hypoglycemic clamp with tirzepatide. Methods: Participants with type 2 diabetes (N=42) were randomized to tirzepatide (15 mg) or placebo for 12 weeks in a crossover design, with a wash-out period of 8-10 weeks. The primary objective was the change in glucagon response during clamp-induced hypoglycemia from plasma glucose (PG) 100 mg/dL to nadir PG (45 mg/dL). Secondary measures were changes in responses of other counterregulatory hormones during clamp-induced hypoglycemia. Time to recovery from the nadir to 72 mg/dL and hypoglycemic symptom scores using the 7-point Edinburgh Hypoglycemia Symptom scale were also assessed. Results: At 12 weeks, HbA1c change from baseline was -1.5% with tirzepatide versus +0.5% with placebo. During induced hypoglycemia, mean PG levels at nadir were 44.5 mg/dL with tirzepatide and 47.5 mg/dL with placebo. Increases in glucagon from PG 100 mg/dL to nadir PG and during recovery from the nadir to 72 mg/dL did not differ between treatments (p=0.756 and p=0.565, respectively). Growth hormone and adrenaline responses did not differ between treatments. Cortisol and noradrenaline responses were delayed with tirzepatide, consistent with lower hypoglycemic symptom scores at nadir observed during tirzepatide treatment periods versus placebo (p=0.007). The proportion of participants aware of hypoglycemia did not differ between treatments. Discussion: The response of the key counterregulatory hormone glucagon to induced hypoglycemia was maintained with tirzepatide.

Keywords: type 2 diabetes, tirzepatide, Counterregulatory response, Hypoglycemia, Clinical Trial

Received: 13 May 2025; Accepted: 04 Aug 2025.

Copyright: © 2025 Pieber, Svehlikova, Urva, Haupt, Zhou, Coskun, Höller, Fluhr, Karanikas, Milicevic and Pratt. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Thomas R. Pieber, Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz, Graz, A-8036, Austria

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